Electronic Common Technical Document
(eCTD) v4.0
TECHNICAL CONFORMANCE GUIDE
Technical Specifications Document
This Document is incorporated by reference into the following
Guidance Document(s):
Guidance for Industry Providing Regulatory Submissions in Electronic Format — Certain Human
Pharmaceutical Product Applications and Related Submissions Using the
eCTD Specifications
For questions regarding this technical specifications document, contact CDER at
esub@fda.hhs.gov or CBER at esubprep@fda.hhs.gov
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
September 2022
ECTD V4
TECHNICAL CONFORMANCE GUIDE
September 2022
2
REVISION HISTORY
DATE
December 2019
January 2021
September 2022
VERSION SUMMARY OF REVISIONS
1.0
Initial Revision
1.1
Revisions based on comments received during a public
comment period.
Changes include removal the following: 1) Two-way
communications and associated data elements; 2)
Regulatory Review Time; 3) Document media type; and
4) Category Event.
1.2
Revisions based on ICH eCTD v4.0 Implementation
package including removal of Transition Mapping
Message and addition of Forward Compatibility.
Added section:
Section 2.1 (Forward Compatibility from eCTD v3.2.2 to
eCTD v4.0)
Removed section:
Section 1.8 (Transition Mapping Message)
3
Table of Contents
1. INTRODUCTION .............................................................................................. 6
1.1
BACKGROUND .............................................................................................................. 6
1.2
PURPOSE ......................................................................................................................... 6
1.3
DOCUMENT REVISION AND CONTROL................................................................... 6
1.4
RELATIONSHIP TO OTHER DOCUMENTS ............................................................... 7
1.5
WHAT’S NEW IN ECTD V4.0 ....................................................................................... 7
1.5.1 SINGLE SUBMISSION UNIT MESSAGE ................................................................. 7
1.5.2 CONTEXT OF USE ..................................................................................................... 7
1.5.3 KEYWORDS ................................................................................................................ 8
1.5.4 CONTEXT GROUPS AND LIFE CYCLE .................................................................. 9
1.5.5 DOCUMENT REUSE ................................................................................................ 12
2. GENERAL GUIDELINES AND CONSIDERATIONS .............................. 13
2.1
FORWARD COMPATIBILITY FROM ECTD V3.2.2 TO ECTD V4.0 ...................... 13
2.2
ECTD SUBMISSION TRACKING INFORMATION .................................................. 14
2.2.1 PRESUBMISSIONS ................................................................................................... 14
2.2.2 ROLLING SUBMISSIONS ....................................................................................... 14
2.2.3 MASTER FILES......................................................................................................... 14
2.2.4 GROUPED SUBMISSIONS ...................................................................................... 15
2.3
ECTD V4.0 MESSAGE-SPECIFIC INFORMATION .................................................. 16
2.3.1 SUBMISSION UNIT TITLE...................................................................................... 16
2.3.2 APPLICATION REFERENCES ................................................................................ 17
2.3.3 CONTACTS ............................................................................................................... 17
2.3.4 DOCUMENT TITLES................................................................................................ 17
2.3.5 STUDY DATA DOCUMENT TYPES ...................................................................... 18
2.4
RESUBMISSION OF NON-ECTD DOCUMENTS ...................................................... 18
3. SUBMISSION CONTENTS............................................................................ 19
3.1
MODULE 1 - ADMINISTRATIVE INFORMATION AND PRESCRIBING
INFORMATION......................................................................................................................... 19
3.1.1 COVER LETTER AND REVIEWER’S GUIDE ....................................................... 19
3.1.2 PATIENT EXPERIENCE DATA .............................................................................. 19
3.1.3 CROSS REFERENCING PREVIOUSLY SUBMITTED INFORMATION THAT IS
NOT IN ECTD FORMAT ...................................................................................................... 20
3.1.4 LABELING................................................................................................................. 20
3.1.5 ADVERTISEMENTS AND PROMOTIONAL LABELING MATERIAL .............. 21
3.1.6 MARKETING ANNUAL REPORTS ........................................................................ 21
3.1.7 INFORMATION AMENDMENTS ........................................................................... 21
3.1.8 FIELD COPY CERTIFICATION .............................................................................. 22
3.1.9 RISK EVALUATION AND MITIGATION STRATEGY (REMS) ......................... 22
4
MODULE 2 – SUMMARIES......................................................................................... 24
3.2
3.2.1 BIOEQUIVALENCE SUMMARY TABLES ............................................................ 24
3.3
MODULE 3 – QUALITY ............................................................................................... 24
3.3.1 LOT DISTRIBUTION DATA .................................................................................... 24
3.3.2 LITERATURE REFERENCES .................................................................................. 24
3.4
MODULE 4 – NONCLINICAL ..................................................................................... 25
3.4.1 STUDY REPORTS ..................................................................................................... 25
3.4.2 LITERATURE REFERENCES .................................................................................. 25
3.4.3 DATASETS ................................................................................................................ 25
3.5
MODULE 5 – CLINICAL .............................................................................................. 26
3.5.1 TABULAR LISTING OF ALL CLINICAL STUDIES ............................................. 26
3.5.2 STUDY REPORTS ..................................................................................................... 26
3.5.3 CASE REPORT FORMS (CRFS) .............................................................................. 27
3.5.4 PERIODIC SAFETY REPORTS ............................................................................... 27
3.5.5 IND SAFETY REPORTS ........................................................................................... 28
3.5.6 LITERATURE REFERENCES .................................................................................. 28
3.5.7 DATASETS ................................................................................................................ 28
4. COMBINATION PRODUCTS....................................................................... 28
5. APPENDIX A: RULES FOR SUBMISSION TRACKING
INFORMATION ..................................................................................................... 32
6. REFERENCES ................................................................................................. 36
7. RELATED REFERENCES ............................................................................ 37
Figures
FIGURE 1: GROUP TITLE DISPLAY ...................................................................................................... 9
FIGURE 2: REPLACING MANY DOCUMENTS WITH ONE IN THE SAME CONTEXT GROUP .................... 10
FIGURE 3: REPLACING ONE DOCUMENT WITH MANY IN THE SAME CONTEXT GROUP ...................... 10
FIGURE 4: REPLACEMENT THAT IS NOT ALLOWED ............................................................................ 11
FIGURE 5: MOVING CONTENT TO A NEW CONTEXT GROUP ............................................................. 12
Tables
TABLE 1: GROUPED SUBMISSION LIMITATIONS AND USE ................................................................ 16
TABLE 2: SUBMISSION TYPE AND DESCRIPTIONS OF USE ................................................................. 32
TABLE 3: SUBMISSION UNIT TYPE AND DESCRIPTIONS OF USE ........................................................ 33
5
eCTD TECHNICAL CONFORMANCE GUIDE
This technical specifications document represents the current thinking of the Food and Drug
Administration (FDA or Agency) on this topic. It does not create any rights for any person and
is not binding on FDA or the public. An alternative approach may be used if it satisfies the
requirements of the applicable statutes and regulations. To discuss an alternative approach,
contact the FDA staff responsible for implementing this specifications document by email at
esub@fda.hhs.gov or esubprep@fda.hhs.gov.
1. INTRODUCTION
1.1 Background
This Electronic Common Technical Document (eCTD) Technical Conformance Guide (Guide)
provides specifications, recommendations, and general considerations on how to submit eCTDbased electronic submissions to the Center for Drug Evaluation and Research (CDER) or the
Center for Biologics Evaluation and Research (CBER). The Guide supplements the guidance for
industry Providing Regulatory Submissions in Electronic Format — Certain Human
Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications
(eCTD Guidance). 1 The eCTD Guidance implements the electronic submission requirements of
Section 745A(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) with respect to
electronic submissions for certain investigational new drug applications (INDs); new drug
applications (NDAs); abbreviated new drug applications (ANDAs); certain biologics license
applications (BLAs); and master files submitted to CDER or CBER. eCTD v4.0 submissions
meet the eCTD requirements defined in the eCTD guidance. These submissions may apply to
combination products with CDER or CBER as the lead center. 2
1.2 Purpose
This Guide provides technical recommendations to sponsors and applicants for the standardized
electronic submission format of INDs, NDAs, ANDAs, BLAs, and master files. The Guide is
intended to complement and promote interactions between sponsors and applicants and FDA’s
electronic submission support staff. However, it is not intended to replace the need for sponsors
and applicants to communicate directly with support staff regarding implementation approaches
or issues relating to electronic submissions. Because of the inherent variability across studies and
applications, it is difficult to identify all issues that may occur related to the preparation and
transmission of electronic submissions. Therefore, prior to submission, sponsors and applicants
should discuss questions with the appropriate center’s electronic submission support staff within
the appropriate center, CDER: esub@fda.hhs.gov or CBER: esubprep@fda.hhs.gov.
1.3 Document Revision and Control
FDA issued an initial Federal Register notice announcing availability of this Guide for public
comment on its contents. Future revisions will be posted directly on the eCTD Web page 3 and the
Found on the FDA eCTD website: https://www.fda.gov/ectd
See 21 CFR Part 3. Combination products are comprised of any combination of a drug and a medical device; a
medical device and a biological product; a biological product and a drug; or a drug, a medical device, and a biological
product. Combination products are assigned to a lead center for review; see 21 CFR 3.4.
3
See above for the eCTD Web page link
1
2
6
revision history page of this document will contain sufficient information to indicate which
sections of this Guide have been revised.
1.4
Relationship to Other Documents
This Guide integrates and updates information discussed previously in the eCTD Guidance and
other specifications documents (including Agency presentations).
This Guide should be considered a companion document to the following:
• Guidance to Industry Providing Regulatory Submissions in Electronic Format —Certain
Human Pharmaceutical Product Applications and Related Submissions Using the eCTD
Specifications 4
• The International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use (ICH) eCTD v4.0 Implementation Package
• ICH Specification for Submission Format for eCTD
• FDA eCTD v4.0 Module 1 Implementation Package
• FDA Study Data Technical Conformance Guide
• FDA Data Standards Catalog
• Specifications for eCTD v4 Validation Criteria
• eCTD v4.0 Comprehensive Table of Contents Headings and Hierarchy
• Portable Document Format (PDF) Specifications
• Example Submissions using eCTD v4 specifications
1.5 What’s New in eCTD v4.0
1.5.1
Single Submission Unit message
The eCTD v4.0 message, submissionunit.xml and submission content, contains all information
necessary to submit a complete sequence to the FDA. The submissionunit.xml is used to organize
both the ICH and Regional sequence content, including the study data that was previously
submitted in a separate Study Tagging xml file.
In addition, there was a change to the overall message structure, the previous eCTD backbone is
replaced by a more dynamic message structure. The eCTD v4.0 message relies heavily on code
lists to manage additional metadata for the submission contents. The eCTD structure is not hard
coded into the message, and only the headings relevant to the sequence need to be submitted with
submission contents.
Refer to the FDA Module 1 eCTD v4.0 Implementation Guide for additional information about
the submission unit message, folder structure and its contents.
1.5.2
Context of Use
The Context of Use is used to place documents under a CTD heading and associated keywords.
The combination of the context of use and keywords create a context group under which one or
4
This document does not currently reflect the eCTD v4.0 requirements.
7
more documents may be placed per the instructions in the M4 Organization of the Common
Technical Document for the Registration of Pharmaceuticals for Human Use guidance for
industry document.
1.5.3
Keywords
Keywords are used to further define the submission content under an eCTD section. Keywords
replace the eCTD 3.2.2 attributes and valid values. This information is more dynamic in the v4.0
message and rules will need to be followed to ensure the required keywords are provided in the
message. Only one keyword of each keyword type should be provided on a heading (i.e., context
of use).
The message contains new keyword code concepts – specifically document type keywords (see
Section 1.5.3.1 in this document) that replace file-tags and sender-defined keywords (see Section
1.5.3.2 in this document) to enable additional organization of content.
1.5.3.1
Document Type Keywords
The document type keywords are a replacement for file-tags to organize study data into additional
headings. Document types will continue to follow the same rules as previous file-tags; however,
they are now provided as keywords. This document will note specific uses of document type
keywords when submitting content to the FDA.
1.5.3.2
Sender-defined Keywords
In the eCTD v4.0 message, keywords may be defined by the submitter using the keyword
definitions. Sender-defined keywords are sent for each application, but it is recommended that
the submitter manages the keyword definitions across applications to enable the use of grouped
submissions. The display name for the keywords greater than 512 characters will be truncated
when displayed to reviewers.
Creating Sender-defined Keywords
Sender-defined keywords should only be sent once for any application. The status of keywords
will always be “active”. Once the keyword definition is established, the value will be displayed
for each Context of Use that references the sender-defined keyword.
1.5.3.2.1
Specific to grouped submissions (see Section 2.2.4 in this document) the sender-defined
keywords should be managed across applications. If the codes assigned to the sender-defined
keywords are not shared across applications, the submitter will not be able to effectively use the
grouped submission option.
Updating Sender-defined Keywords
Updates to sender-defined keywords should be made only when there is a typo or error in the
value. A new keyword definition should be submitted if there is a new sender-defined keyword
that needs to be used.
1.5.3.2.2
8
Updating the value of a sender-defined keyword will change its value for all uses of that keyword
definition – i.e., the change will take effect across submission units in that application. The
change should also be applied to all applications using the keyword definition.
Group Title Keywords
Group title keywords are new in eCTD v4.0 and are a type of sender-defined keywords. The
group title keyword allows the submitter to create further organization of documents under
specified headings that allow for more than one document (as specified in the M4 Organization of
the Common Technical Document for the Registration of Pharmaceuticals for Human Use
guidance in industry 5).
1.5.3.2.3
Documents associated with a group title will be displayed separately under the eCTD heading and
other associated keywords. The group title keyword will be applied to the lowest heading level.
The figure below depicts the use of two group titles and is achieved by sending two different
context of uses with the same heading value, but different group title keywords.
Figure 1: Group Title Display
The group title keyword is not intended to replace other specified keywords – it is only intended
to allow for the further organization of content where multiple documents are combined to
provide information for a specific topic area. This keyword should be used sparingly for this
specific purpose.
1.5.4
Context Groups and Life Cycle
In the eCTD v4.0 message, a context group is the combination of the context of use and keywords
used to place a document under an eCTD section. Context groups require that the context of use
5
Also represented in the ICH eCTD v4.0 code lists.
9
and keyword combinations stay the same when submission content is replaced. The replace
function will track the changes made to the submission contents when one document (referenced
by a context of use) is replaced by one, many, or many to one. The figures below depict the
document life cycle in a context group.
Figure 2: Replacing Many Documents with one in the same Context Group
Figure 3: Replacing One Document with many in the same Context Group
If the context group is not the same, the replacement is not allowed. The figure below depicts
many documents replacing one document from a prior sequence in a different context group.
10
Figure 4: Replacement that is not allowed
The context groups are intended to keep content organized and life cycle maintained in an
application. Providing the content to the incorrect section in the eCTD will result in the content
not being displayed in the expected location for the reviewers. Therefore, if the heading
placement or keywords need to change for the referenced submission contents – a new context
group shall be created and the old context group should be suspended as follows:
• Create a new submission unit message.
• Use the status of “suspend” to inactivate all the content that was incorrectly referenced in
the section.
• Reference the documents using a new context of use, ensuring that the keywords (e.g.,
‘name’, ‘manufacturer’, ‘dosage form’, ‘study id study title’) are an exact match to the
section the documents should be placed.
• Resubmission of the files and document elements is not necessary as it is referenced by
the document’s unique identifier.
The figure below depicts the submission contents that are suspended and those submitted under a
new context group (i.e., the new CTD heading and/or keywords). Note that the content under
the new context group will not be related to the previous content, however document reuse may
be applied (See Section 1.5.5 in this document for Document Reuse).
11
Figure 5: Moving Content to a New Context Group
1.5.5
Document Reuse
The eCTD v4.0 message may contain references to documents previously submitted in separate
applications by referencing the document’s unique identifier. Therefore, a document can be
referenced without including the physical file in the new message. The content will be displayed
from the document repository 6 instead of relying on the sequence physical folder structure to
contain all the files referenced in the message. When submitting a reference to an existing
document, it is important to ensure that all document hyperlinks are relevant to the new context of
use.
6
Documents cannot be reused across the CDER and CBER document repositories.
12
2.
GENERAL GUIDELINES AND CONSIDERATIONS
The following subsections provide general guidelines and considerations for additional
information in the eCTD v4.0 message.
2.1 Forward Compatibility from eCTD v3.2.2 to eCTD v4.0
Forward Compatibility is used for any dossier that has v3.2.2 content and the application is being
converted to a v4.0 message.
Please note that forward compatibility will not be implemented in the first phase of
eCTD v4.0 implementation. Consult the FDA eCTD v4.0 website for updates to the
eCTD v4.0 implementation timelines.
The submitter should take into consideration the following submission requirements and
recommendations when converting to eCTD v4.0:
•
•
•
•
•
•
•
When submitting the first eCTD v4.0 sequence to an eCTD v3.2.2 dossier the next
available sequence number is submitted as a whole number. For example, if the last
eCTD v3.2.2 message has a sequence number “0003”, the first eCTD v4.0 submission unit
will be sequence number “4”.
Submissions should be coded according to the current regulatory activity. If the
submission is a continuation of an open regulatory activity, the initial sequence number is
needed to link the submission to the v3.2.2 regulatory activity. The v3.2.2 sequence
number should only be submitted to the first eCTD v4.0 submission for the open
regulatory activity.
Once a v4.0 submission unit has been received for an application, all future sequences
must be sent in v4.0 – i.e., a v3.2.2 message received after the initial v4.0 message is
received will be rejected.
All v3.2.2 applications included in an eCTD v4.0 Grouped Submission will be converted
to v4.0 messages.
When submitting v4.0 content that should be grouped with v3.2.2 content the keyword
codes and values must match.
Consider a strategy across applications for sender-defined keywords, especially in the case
of grouped submissions. Keyword Definitions need to be established prior to or during the
submission of a Grouped Submission in eCTD v4.0.
Understand specific requirements that require changes to the current eCTD v3.2.2
attributes provided – e.g., study id and study title.
Forward Compatibility enables life cycle and document reuse of v3.2.2 content, the submitter
should take into consideration the following requirements:
• The “Leaf Reference” is used to life cycle and reuse v3.2.2 content.
• Document reuse includes content previously submitted in eCTD v3.2.2 within or across
applications, including applications that have not been converted to v4.0.
• Life Cycle
13
Life cycle of submission content is only allowed for active (e.g., new, replace) leaf
elements (i.e., content that is in the current view).
o Suspend eCTD v3.2.2 content (i.e., to inactivate content) within an application.
o When v3.2.2 content is replaced, it must follow v4.0 context group life cycle rules; the
headings and attributes remain the same when replacing content by sending the same
values in the new eCTD v4.0 keyword and context of use.
o
Refer to the ICH eCTD v4.0 Implementation Guide and FDA Module 1 eCTD v4.0
Implementation Guide for additional information about the Forward Compatibility.
2.2 eCTD Submission Tracking Information
The rules for submission tracking information (i.e., the allowable application types for the
submission) are presented in Section 5 of this document and specific guidance is provided in the
subsections below.
2.2.1
Presubmissions
Any information submitted in eCTD format before the original application or supplement
submission (specifically for NDA, ANDA and BLAs), should be coded with a submission unit
type value of “presubmission” and the first submission unit to an application should start with a
sequence number of 1. Any presubmissions to a subsequent supplement application should start
with the next available sequence number in the application.
Note: Refer to Section 2.1 for additional guidance for open regulatory activities.
2.2.2
Rolling Submissions
Rolling submissions are allowed for an NDA or BLA. The submission type for the set of
submission units transmitted before the application is complete are managed the same as
presubmissions to the original application until it is ready for review. The rolling submission
should be coded with a submission type value for “original application” and submission unit type
value for “presubmission”. The cover letter and form should state “presubmission to rolling
submission – part 1 of XXX” (depending on how many parts before the final submission).
The final submission unit completing the application should be coded with a submission type
value for “original application” and submission unit type value for “application” to start the
respective review clock. The cover letter and form of the final submission should state "original
application – part XXX of XXX of rolling submission".
2.2.3
Master Files
For information on Drug Master File submissions, including Letters of Authorization,
please refer to the Drug Master File website (https://www.fda.gov/drugs/forms-submissionrequirements/drug-master-files-dmfs).
14
2.2.4
Grouped Submissions
A grouped submission is also known as a global supplement, global submission, bundled
supplement, bundled submission, multiple product submission or trans-BLA. This type of
submission eliminates the need to submit multiple, identical submissions to different applications.
The documents referenced in the grouped submission are applied to all applications identified.
The grouped submission concept does not replace or affect previously existing cross-referencing
functionality (use of m1.4.4 or cross application reference links).
A grouped submission contains a single submissionunit.xml that contains all application numbers
and their respective sequence numbers in the group. For each unique application number in the
group, only one sequence number should be provided for each regulatory activity.
Refer to the FDA Module 1 eCTD v4.0 Implementation Guide for additional information about
Grouped Submissions.
The following items listed below provide general information and use limitations for submitting a
grouped submission to multiple applications 7:
General Information:
• Initial grouped submissions should only include new context of uses.
• When using life cycle operations of suspend or replace in a subsequent grouped submission,
the life cycle operation will apply to all context of use in all submissions referenced in the
grouped set of applications.
• The grouped submission’s content must reside in the same exact location within the eCTD
structure for all applications included in the group.
Consider Forward Compatibility when establishing Grouped Submission in eCTD v4.0. Refer
to Section 2.1.
Use Limitations 8:
• Only one application type can be used for all applications in a grouped submission.
• Only one submission type can be used for all regulatory activities in a grouped submission.
Electronic consideration(s) for grouped submissions will not supersede the policy and practice of bundled
submissions as it may or may not affect user fees per the Guidance for Industry: Guidance for Industry Submitting
Separate Marketing Applications and Clinical Data for Purposes of Assessing User Fees.
8
See Table 1 “Grouped Submission Limitations and Use” for further restrictions.
7
15
Table 1: Grouped Submission Limitations and Use
Center Acceptance of
Application Types
Grouped Submission
Submission Types Allowed
Allowed
CDER
CBER
Labeling Supplement,
Chemistry Manufacturing Controls Supplement,
Product Correspondence,
Promotional Labeling Advertising,
REMS Supplement
Efficacy Supplement,
Labeling Supplement,
Chemistry Manufacturing Controls Supplement,
Product Correspondence,
Promotional Labeling Advertising,
REMS Supplement
Product Correspondence
YES
NO
YES
YES
YES
NO
IND
Annual Report,
Product Correspondence
YES
NO
NDA
Efficacy Supplement,
Labeling Supplement,
Chemistry Manufacturing Controls Supplement,
Product Correspondence,
Promotional Labeling Advertising,
REMS Supplement
YES
NO
ANDA
BLA
MF
2.3 eCTD v4.0 Message-specific Information
2.3.1
Submission Unit Title
9
The title of the submission unit is optional and does not restrict the number of characters
allowed, but only the first 128 characters will be displayed to reviewers. Therefore, the value
provided for the submission unit title should be a high-level description of the submission’s
purpose and should also help differentiate between similar types of submission units or
sequences.
Some examples of helpful submission descriptions are listed below:
• Supplement provides for new manufacturing site
• New site for Active Pharmaceutical Ingredient (API) manufacture, DSM Ltd, Groningen,
NL
• Proposed indication of an efficacy supplement
• Pharmtox Information Amendment – Final Study Report A1001
• Clinical Information Amendment – New Protocol A001100
• Response to an Information Request (IR) letter and date.
9
In eCTD v3.2.2 this was included as the “submission-description”.
16
•
Type of amendment (clinical – new protocol, clinical – protocol amendment,
pharmacology, toxicology, etc.)
The title should not:
• contain a response to FDA inquiries
• replace the cover letter
• pose questions to the FDA
• contain information that is in support of an application or is needed in the approvability or
acceptability of an application, or
• contain information that is critical or needs to be reviewed.
2.3.2
Application References
Application references 10 should be provided when an application references other applications
(e.g., Drug Master File). A cross-reference only needs to be identified in one submission unit file.
2.3.3
Contacts
The eCTD v4.0 message may contain multiple contacts for a regulatory activity/submission. The
contacts that can be submitted to the FDA include the following:
• Regulatory Contact 11 – this is an individual that the FDA Regulatory Project Manager
will contact regarding submission/regulatory activity status.
• Technical Contact – this is an individual that the FDA technical staff will contact when
there is an issue with the technical aspects of the eCTD v4.0 message (e.g., structure and
content of the XML message and/or submission files).
• United States Agent – this is an individual acting on behalf of the submitter to submit
information to the FDA.
Contacts should be sent once for each regulatory activity and updated as necessary.
2.3.4
Document Titles
Document titles 12 are displayed to the reviewer when viewing an eCTD application. Although
some eCTD viewing tools list file names, the two are not related. All modules of the eCTD
should contain descriptive eCTD document titles that are short, meaningful, and indicative of
each document's content. The eCTD section number should not be included in the document
title.
For documents of the same type (e.g., cover letter, Form FDA 356h, and annual report
documents), additional information should be provided in the document title so reviewers can
distinguish documents submitted in different sequences. For example, the document title for a
cover letter should also include the date (e.g., 2016-12-31). Additionally, if documents of the
same type are being provided in different file formats, a file format (e.g., “MS Word”) should be
In eCTD v3.2.2 this was included as the “cross-reference-application-number”
The Regulatory Contact may be specific to the submission type – e.g., Promotional Labeling and Advertising
Regulatory Contact. Refer to the controlled vocabulary files for the possible regulatory contact types.
12
In eCTD v3.2.2 this was termed “leaf title”
10
11
17
included at the end of the document title. This helps reviewers quickly identify which software
applications are necessary to open the files.
Per eCTD Guidance (Providing Regulatory Submissions in Electronic Format — Certain
Human Pharmaceutical Product Applications and Related Submissions Using the eCTD
Specifications 13), when naming folders and files, the length of the entire path must not exceed
180 characters. The character limit on the document title field is 512 characters.
2.3.5
Study Data Document Types
In eCTD v4.0 the file-tags have been changed to keywords. Specifically, document type
keywords are used to further describe submission content. Document type keywords are required
for all files in Section 4.2.x and 5.3.1.x – 5.3.5.x. Document Types are not required for 4.3
Literature references, 5.2 Tabular listings, 5.4 Literature references and 5.3.6 Postmarketing
reports. These documents may be submitted as single separate files without a document type
keyword.
2.4 Resubmission of non-eCTD documents
In general, resubmission of previously submitted content is neither necessary nor encouraged.
However, there are occasional circumstances in which a “baseline” submission is helpful to the
reviewer. One example is CMC information contained in module 3. In a circumstance such as
this, the FDA will accept the resubmission of non-eCTD content (e.g., paper, eNDA) but the
previously submitted content should be submitted as a separate submission, as opposed to being
included in a supplement or an amendment to a regulatory activity. The cover letter should state
that the submission contains only previously submitted content and certify that the sequence
does not include any changes or updates to the application. For marketing applications, the
certification should include a table with a listing of approvals that relate to the content being
resubmitted. For INDs and master files, the list should include amendments that relate to the
content being resubmitted.
In most cases, the submission of a “baseline” or other previously submitted content will require
that the previous content be reorganized to meet the eCTD format requirements. You should not
resubmit the previous content “as-is” unless the content was in the CTD format and the eCTD
backbone was not used when content was originally submitted.
The submission type should be coded as “Product Correspondence”. On the 356h form, you
should select “Product Correspondence” for the Submission type and enter “Submission of
previous non-eCTD content in the eCTD format”.
Prior to resubmitting content, you should contact the responsible review division to determine if
resubmission is acceptable.
13
This document does not currently reflect the eCTD v4.0 requirements.
18
3.
SUBMISSION CONTENTS
The following section will provide specific guidance on the submission contents of a submission
unit and any instructions for the submission unit message.
3.1 Module 1 - Administrative Information and Prescribing Information
Module 1 includes, but is not limited to: administrative, labeling, REMS, and promotional
material documents. The subject matter for each document should be assigned to the lowest
level of the hierarchy outlined in the associated FDA technical specification Comprehensive
Table of Contents Headings and Hierarchy 14. (Note that some headings apply only to specific
applications or specific submission types.)
3.1.1
Cover Letter and Reviewer’s Guide
Cover letters contain pertinent information which aid communication within the review process.
It is recommended that the cover letter include the following information:
• Regulatory description of the submission, including appropriate regulatory information,
and any desired hyperlinks to submitted information
• Technical description of the submission, including the approximate size of the
submission (e.g., 2 gigabytes)
• Statement that the submission is virus free, with a description of the software (name,
version, and company) that was used to check the files for viruses
• A regulatory and technical point of contact for the submission, including email address.
A reviewer’s guide 15 is beneficial when accompanying an original NDA, BLA, or combination
product 16 application. The reviewer’s guide should include a high-level overview of the
submission with hyperlinks to submitted information. The reviewer’s guide should not contain a
copy of the eCTD table of contents. Rather, an outline format describing the submission's
content is preferred, including tables or lists, and avoiding a continuous narrative description of
the application’s content.
The reviewer’s guide should be provided as a document separate from the cover letter and placed
in Section 1.2 of the eCTD with a descriptive document title.
3.1.2
Patient Experience Data
If submitting patient experience data as part of an application for marketing approval, the
following table should be populated and included in the Reviewer’s Guide (section 1.2).
Patient experience data (e.g., clinical outcome assessments) collected as part of a clinical
trial should be submitted as part of the relevant clinical trial data. Other patient
https://www.fda.gov/media/150309/download
This is different than a Study Data Reviewer’s Guide (SDRG). Additional information on the SDRG can be found
in the Study Data Technical Conformance Guide located on at: https://www.fda.gov/industry/fda-resources-datastandards/study-data-standards-resources
16
See additional recommendation for combination products in Section 4 of this document
14
15
19
experience data that is separate from clinical trials should be submitted to section 5.3.5.4
o
The patient experience data that was submitted as part of the
application, include:
o
o
o
o
o
o
o
Clinical outcome assessment (COA) data, such as
o Patient reported outcome (PRO)
o Observer reported outcome (ObsRO)
o Clinician reported outcome (ClinRO)
o Performance outcome (PerfO)
Qualitative studies (e.g., individual patient/caregiver
interviews, focus group interviews, expert interviews,
Delphi Panel, etc.)
Patient-focused drug development or other stakeholder
meeting summary reports
Observational surveys studies designed to capture patient
experience data
Natural history studies
Patient preference studies (e.g., submitted studies or
scientific publications)
Other: (Please specify)
The patient experience
data that was submitted
as part of the application,
include:
3.1.3
Cross Referencing Previously Submitted Information that is not in eCTD
Format
If reference to a non-eCTD submission is needed, place a cross-reference document (e.g., table
showing where to find non-eCTD documents) in Section 1.4.4 of the eCTD. The information in
the document should include:
• the application number
• the date of submission (e.g., letter date)
• the file name (if applicable)
• the page number (if necessary)
• the submission identification (e.g., submission number, volume number if paper,
electronic folder if applicable) of the referenced document.
3.1.4
Labeling
This section describes how to provide specific labeling documents:
Labeling History
A history that summarizes labeling changes should be provided as a single PDF file. The
history summary should include the following information:
• Complete list of the labeling changes being proposed in the current submission and the
explanation for the changes
• Date of the last approved labeling
20
•
•
History of all changes since the last approved labeling (with each change, note the
submission that originally described the change and the explanation for the change)
List of supplements pending approval that may affect the review of the labeling in the
current submission.
Content of Labeling
The FDA guidance for industry Providing Regulatory Submissions in Electronic Format —
Content of Labeling 17 gives details on providing the content of labeling files.
Labeling Samples
Each labeling sample (e.g., carton labels, container labels, package inserts) should be provided
as an individual PDF file. The samples should:
• Include all panels, if applicable
• Be provided in their actual size, and
• Reflect the actual color proposed for use.
3.1.5
Advertisements and Promotional Labeling Material
As described in the guidance for industry “Providing Regulatory Submissions in
Electronic and Non-Electronic Format--Promotional Labeling and Advertising Materials
for Human Prescription Drugs”, certain types of promotional-material-related
submissions, including postmarketing submissions of promotional materials are required
to be submitted in eCTD format.
While HTML (a commonly used file type for websites) is an acceptable file format type
to use for eCTD Module 1 promotional submissions, submission of HTML files that
depend on JavaScript, PHP or server-side scripts that generate dynamic content should
not be submitted because these dependent files are not on the list of acceptable file format
types. An acceptable alternative for these types of HTML files is to utilize PDF. Please
refer to the PDF Specifications for details. 18
3.1.6
Marketing Annual Reports
A bookmark should be included for each study or trial described in the postmarketing
requirement/commitments files. The reporting period covered by the annual report should be
included in the eCTD document title (e.g. Status of Postmarketing Study Commitments MMDDYY-MMDDYY).
3.1.7
Information Amendments
Documents for information amendments should be included in the applicable eCTD module
using the appropriate eCTD heading to describe the document’s subject matter.
This document does not currently reflect the eCTD v4.0 requirements.
See “Special Considerations for Promotional, Labeling, and Advertising Material” in the Portable Document
Format (PDF) Specifications located in the eCTD Submission Standards catalog. The catalog is located on the FDA
eCTD website (https://www.fda.gov/ectd)
17
18
21
Section 1.11 may be used for submission of responses to Information Requests (IR), where the
information being submitted does not fit under any heading in Module 2, 3, 4 or 5. The IR
response should be submitted under the appropriate subheading 1.11.1 – 1.11.3 within Section
1.11, for quality, nonclinical, or clinical information, respectively. The subheading 1.11.4 for
multiple module information should be used if the IR response covers multiple subject areas.
If the IR response impacts documents submitted in Modules 2 – 5, the new or replacement
documents should be submitted to the appropriate location in Module 2 – 5 and referenced in
the document from Section 1.11.
3.1.8
Field Copy Certification
For marketing applications, the Field Copy Certification (i.e., a copy of the letter described
below) should be included with the electronic application in Section 1.3.2 of the eCTD. The
District office should be notified by letter that the eCTD submission will be submitted to FDA,
and because the field offices have access to the complete submission on the FDA network, an
individual field copy is no longer required. The letter should include:
• Drug and application number
• FDA center and division
• Application is in eCTD format.
3.1.9
Risk Evaluation and Mitigation Strategy (REMS)
A REMS supplement is a supplemental application proposing a new REMS or modifications
(major and/or minor) to an approved REMS.
Use the submission type of REMS Supplement in the submissionunit.xml and select REMS
supplement on the 356h form.
If the REMS supplement is part of another supplement, the submission type should be coded with
the appropriate supplement type (e.g., efficacy, CMC). On the 356h form, you should select both
supplements for the submission type.
REMS assessments, REMS revisions, and REMS correspondences are not supplements, and the
submission type should be coded as “product correspondence”. On the 356h form, you should
select “other” for the submission type.
The following table is provided to assist applicants on where to place documents under the eCTD
Module 1 REMS 1.16 sub-headings.
eCTD Section
Heading
1.16.1 Risk
Management
(Non-REMS)
eCTD Section: 1.16 Risk Management
Description
Applicants should place risk management plans (RMP), risk
minimization action plans (RiskMAPs), and RiskMAP reports under
this heading. Submission of a Risk Evaluation and Mitigation
Strategy (REMS) should not be placed under this heading as REMS
are to be included under heading 1.16.2. However, if the applicant is
22
eCTD Section
Heading
eCTD Section: 1.16 Risk Management
Description
submitting a rationale for not submitting a proposed REMS, it
should be placed here
1.16.2 Risk
Evaluation and
Mitigation
Strategy (REMS)
Do not include any files under this heading. The files should be
specific for the lowest level of the hierarchy outlined in the FDA
technical specification Comprehensive Table of Contents Headings
and Hierarchy available on our eCTD Website 19and provided
below for sub-heading 1.16.2.
1.16.2.1 Final
REMS
The final REMS document, all REMS materials in their final format,
and the REMS supporting document (for original REMS, REMS
modifications, and REMS revisions) 20 should be submitted in
Microsoft Word and PDF format.
FDA can also accept the REMS document in Structured Product
Labeling (SPL) format. If you intend to submit the REMS document
in SPL format, as soon as possible, but no later than 14 days from
the approval, submit the REMS document in SPL format using the
FDA automated drug registration and listing system (eLIST).
For more information on submitting REMS in SPL format, please
email, REMS_Website@fda.hhs.gov.
1.16.2.2 Draft
REMS
1.16.2.3 REMS
Assessment
The proposed REMS document, all REMS materials, and the REMS
supporting document in clean and track changes (for original
REMS, REMS modifications, and REMS revisions) should be
submitted in Microsoft Word format as individual files. If certain
documents, such as enrollment forms, are only in PDF format, they
may be submitted as such, but the preference is to include as many
as possible in Word format.
Applicants can also submit the proposed REMS document in SPL
format. If you intend to submit the proposed REMS document in
SPL format, include the SPL file with your proposed REMS
submission. The REMS SPL file should be referenced in the eCTD
xml backbone under Section 1.16.2.2. The REMS SPL file should
be placed in a folder named “spl”, along with copies of any REMS
materials referenced in the REMS SPL file.
Applicant’s REMS assessment report, abbreviated REMS
assessment for an efficacy supplement, and responses to FDA
https://www.fda.gov/media/150309/download
See draft Guidance for Industry Risk Evaluation and Mitigation Strategies: Modifications and Revisions, available
at: https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
19
20
23
eCTD Section
Heading
1.16.2.4 REMS
Assessment
Methodology
1.16.2.5 REMS
Correspondence
1.16.2.6 REMS
Modification
History
eCTD Section: 1.16 Risk Management
Description
“Requests for Information or Comments,” that are associated with
an assessment should be placed here.
Any survey or other methodology used to assess the REMS should
be placed here.
Official REMS related correspondence to the FDA that is not
associated with a submission under review should be placed
here. Applicants’ responses to FDA “Requests for Information
or Comments,” that are associated with a REMS supplement or
an assessment that is under review should be included under
applicable sub-headings.
It is recommended that applicants submit a REMS history that
summarizes all type of changes (revisions, minor modifications, and
major modifications) made to the REMS since its approval. 21 The
REMS history should be in tabular format similar to the history of
labeling changes and submitted as a single PDF file.
3.2 Module 2 – Summaries
3.2.1
Bioequivalence Summary Tables
For ANDAs, Bioequivalence Summary Tables should be provided in Section 2.7.1 of the
eCTD. Additional information about ANDA submissions is available on the ANDA Forms
and Submission Requirements Web page located at:
https://www.fda.gov/drugs/abbreviated-new-drug-application-anda/abbreviated-new-drugapplication-anda-forms-and-submission-requirements.
3.3
Module 3 – Quality
3.3.1
Lot Distribution Data
Lot distribution data should be submitted for BLAs according to the guidance for industry
Electronic Submission of Lot Distribution Reports available at:
https://www.fda.gov/media/89610/download
3.3.2
Literature References
The files pertaining to key literature references should be provided as individual PDF files in
Section 3.3 of the eCTD. The document titles should be short and meaningful (e.g., eCTD
document title: SmithJA 2002 Impurities).
See draft Guidance for Industry Risk Evaluation and Mitigation Strategies: Modifications and Revisions, available
at: https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs for a more detailed
description of the REMS history
21
24
3.4
Module 4 – Nonclinical
The organization of Module 4 is the same for all applications and related submissions. The
guidance provided below addresses general considerations for the submission contents (i.e., the
physical files and folders) and the contents of the message (i.e., the additional metadata for the
submission contents – e.g., headings and keywords). In addition, specific topics have additional
guidance to ensure complete submission of contents.
The documents for Module 4 should be placed in the m4 folder. The subject matter for each
document should be specific for the lowest level of the hierarchy outlined in the FDA technical
specification Comprehensive Table of Contents Headings and Hierarchy 22. The headings for
study reports should also be specific for the lowest level of the hierarchy. Each document
should be provided as an individual PDF file (or appropriate file format for study data).
Module 4 includes specific keywords (e.g., document type keywords) that are included in the
eCTD v4.0 code lists and are required by the eCTD guidance.
3.4.1
Study Reports
Typically, a single document should be provided for each study report included in this module.
However, if the study reports are provided as multiple documents, the subject matter of each
document should be confined to a single item from the list provided in the FDA technical
specification Comprehensive Table of Contents Headings and Hierarchy 23.
In the following examples, study reports should be provided as separate (granular) documents:
•
•
Documents previously submitted within an application: If a document has been
provided in a previous submission (e.g., referencing a previously provided protocol), the
applicant should provide only an eCTD document reference to the protocol and not
resubmit the protocol document.
Inclusion of additional information: Study reports should be provided as separate
documents. Additional information (e.g., audit information or a publication based on
the study) should be provided as a separate file, rather than replacing the entire study
report.
3.4.2
Literature References
Each literature reference should be provided as an individual PDF file in Section 4.3 of the
eCTD. The file names and eCTD document titles should be short and meaningful (e.g., eCTD
document title: SmithJA 2002 Impurities).
3.4.3
Datasets
The FDA technical specifications document Study Data Technical Conformance Guide
provides details on the submission of datasets and related files (e.g., data definition file,
22
23
https://www.fda.gov/media/150309/download
Ibid.
25
program files). 24 Datasets should be provided only in modules 3-5 of the eCTD. Updated
datasets should “replace” the old dataset.
3.5 Module 5 – Clinical
The organization of Module 5 is the same for all applications and related submissions. The
guidance provided below addresses general considerations for the submission contents (i.e., the
physical files and folders) and the contents of the message (i.e., the additional metadata for the
submission contents – e.g., headings and keywords). In addition, specific topics have additional
guidance to ensure complete submission of contents.
The documents for Module 5 should be placed in the m5 folder. The subject matter for each
document should be specific for the lowest level of the hierarchy outlined in the FDA technical
specification Comprehensive Table of Contents Headings and Hierarchy 25. The headings for
study reports should also be specific for the lowest level of the hierarchy. Each document
should be provided as an individual PDF file (or appropriate file format for study data).
Module 5 includes specific keywords (e.g., document type keywords) that are included in the
eCTD v4.0 code lists, and are required by the eCTD guidance.
Refer to the ICH eCTD v4.0 Implementation Package for additional information on the eCTD
v4.0 controlled vocabulary.
3.5.1
Tabular Listing of All Clinical Studies
The tabular listing of all clinical studies should be provided as a single PDF file in Section 5.2
of the eCTD. For ease of review, hyperlinks to the referenced studies in m5 should be
provided. Document type keywords do not apply to the tabular listing of clinical studies.
3.5.2
Study Reports
Typically, a single document should be provided for each study report included in this section.
However, if the study reports are provided as multiple documents, the subject matter of each
document should be confined to a single item from the list provided in the FDA technical
specification Comprehensive Table of Contents Headings and Hierarchy 26.
In the following scenarios, study reports should be provided in the following manner:
•
•
Documents previously submitted within an application: If a document has been
provided in a previous submission (e.g., referencing a previously provided protocol), the
applicant should provide only an eCTD document reference to the protocol and not
resubmit the protocol document.
Inclusion of additional information: Study reports should be provided as separate
documents and any additional information (e.g., audit information or a publication based
on the study) should be provided as a separate file, rather than replacing the entire study
https://www.fda.gov/media/150309/download
Ibid.
26
Ibid
24
25
26
report.
Typically, study reports should be provided according to the FDA guidance for industry ICH
E3 Structure and Content of Clinical Study Reports. The individual documents that should be
included in a study report are listed in the FDA technical specification Comprehensive Table of
Contents Headings and Hierarchy 27. In the case where no other document type is appropriate,
the “study report body” document type may be used.
In cases when a legacy report has already been prepared as a single electronic document, the
entire study report should be provided as a single document, not including the case report forms
(CRFs) (see Section 3.5.3 in this document) and individual data listings. The document type of
“legacy clinical study report” should be used for this type of study report.
Human Factors Study reports should be placed in Module 5.3.5.4 Other Study Reports and
Related Information and should include the appropriate human factors document type keywords
(e.g., hf validation protocol, hf validation report, hf validation other) to describe the document’s
contents.
3.5.3
Case Report Forms (CRFs)
An individual subject’s complete CRF should be provided as a single PDF file. If a paper CRF
was used in the clinical trial, the electronic CRF should be a scanned image of the paper CRF
including all original entries with all modifications, addenda, corrections, comments,
annotations, and any extemporaneous additions. If electronic data capture was used in the
clinical trial, a PDF-generated form or other PDF representation of the information (e.g.,
subject profile) should be submitted.
The subject’s unique identifier should be used as the title of the document and the file name.
These names are used to assist reviewers in finding the CRF for an individual subject. Each
CRF must have bookmarks as part of the comprehensive table of contents required under
21 CFR 314.50(b). Each CRF domain and study visit should be bookmarked to assist reviewers
in their review of CRFs. For addenda and corrections, avoid confusion by making a hypertext
link from the amended item to the corrected page or addendum. Bookmarks for these items
should be displayed at the bottom of the hierarchy.
Each CRF should be included with its corresponding clinical study report and should include a
document type of ‘case report forms’. FDA does not use the eCTD heading 5.3.7 for CRFs,
therefore documents should not be placed under this heading.
3.5.4
Periodic Safety Reports
Periodic safety reports 28 consist of two parts: a descriptive portion and the individual case
safety reports (ICSRs). Only the descriptive portion of the periodic report may be submitted to
the eCTD.
https://www.fda.gov/media/150309/download
Periodic adverse drug experience reports or periodic adverse experience reports, as described in 21 CFR 314.80
and 600.80, respectively.
27
28
27
The descriptive portion of the report may be sent as either the periodic adverse (drug)
experience report (PADER) or the ICH-E2C periodic safety update report (PSUR) (allowed
with approved waiver). Either format may be submitted to the eCTD in Section 5.3.6 as an
individual PDF file without any document type keywords. Include the reporting period in the
document title.
Do not submit ICSR E2B formatted XML files in eCTD.
3.5.5
IND Safety Reports
Each individual IND safety report with its associated study should be provided in Section 5.3 of
the eCTD. Document titles that clearly relate to the individual cases should use "Safety Report"
along with "initial" or "follow-up", depending on the content of the individual safety report.
Each IND safety report should be described by using the document type keyword of ‘safety
report’ and should be submitted as “new” without replacing any previously submitted
information.
For additional details on providing IND safety reports, refer to the FDA guidance for industry
Safety Reporting Requirements for INDs and BA/BE Studies.
3.5.6
Literature References
Provide each literature reference as an individual PDF file in Section 5.4 of the eCTD, as
appropriate. The document titles should be short and meaningful (e.g., eCTD document title:
SmithJA 2002 Impurities).
3.5.7
Datasets
The FDA technical specifications document Study Data Technical Conformance Guide
provides details on the submission of datasets and related files (e.g., data definition file,
program files). 29 Datasets should be provided only in modules 3-5 of the eCTD. Updated
datasets should “replace” the old dataset.
4.
COMBINATION PRODUCTS 30
Generally, drug or biological product information for combination drug and device product
information and related engineering and manufacturing information should be located in the
same eCTD sections that would provide similar information for the drug or biological product
alone. This particularly applies to device constituent parts that also serve as the drug container
closure system. For example, the M3 quality module should contain information on such
device constituents in Section 3.2.P.7 and the message may include a keyword for the
“container” type. Supportive documents for container closure device constituents should be
Available at https://www.fda.gov/industry/fda-resources-data-standards/study-data-standards-resources.
As set forth in 21 CFR part 3, a combination product is a product composed of any combination of a drug, device,
or biological product.
29
30
28
placed in Section 3.2.R. For other types of device constituent parts that do not have a logical
location within 3.2.P, the information should be placed in 3.2.R. For example, quality data for
a free standing laser would be in 3.2.R. Quality information on the combination product as a
whole (not the separate constituent parts) should be located in 3.2.P with appropriate hyperlinks
to 3.2.R. The following recommendations should be followed by sponsors/applicants for
combination products: 31
1. General format comments
a. Use of eCTD headings: Adhere to eCTD headings as defined in the FDA technical
specification Comprehensive Table of Contents Headings and Hierarchy 32.
b. Group titles may be used in this section to provide additional organization to the
submission contents
c. Document titles: As there are no-subheadings permitted under 3.2.R, when placing
combination product files in this section, prefix the document title with “DEVICE”
as this will help the reviewer differentiate between combination and other categories
of files.
2. Module 1, Section 1.2
To facilitate the review, a reviewer’s guide should be provided in Section 1.2 cover
letters. The reviewer’s guide is separate and referenced from the cover letter. It should
provide a high-level overview (with reference links) of the submission’s content and
should list the location of information in the eCTD. 33 For example, it should identify
where drug, device, and combination product information is located. Additionally, the
reviewer’s guide should identify the location of information that cannot be further
identified within the electronic format. This particularly applies to the following:
• Documents that are not currently listed as numerical items in ICH and FDA
specifications and guidance documents (e.g., Comprehensive Table of Contents
Headings and Hierarchy 34). For example, the reviewer’s guide should provide
reference links to each document in Section 3.2.R.
• Sections which are repeated through the use of different keywords (e.g. =
product name “Albuterol; product name = “Dry Powder Inhaler”).
3. Module 1.1. Forms
Form 356h should identify all facilities involved in the manufacture and testing of the
combination product (drug, device, drug-device combination). Also, see item 4.a below
for additional information in Section 3.2.P.3 Manufacture
FDA recognizes the breadth of combination product designs. The information in this guide is to promote
consistency and facilitate timely review. The agency recommends that applicants, who wish to provide data in a
different location, should contact the review division for discussion. Applicants that wish to continue to use a
location based on legacy submissions for the same application may continue to use that location.
32
https://www.fda.gov/media/150309/download
33
If referencing previously submitted information not in the eCTD format, see Section 3.1.3 of this guide- “Cross
Referencing Previously Submitted Information that is not in eCTD Format”
34
https://www.fda.gov/media/150309/download
31
29
4. Module 3
a.
Section 3.2.P.3 Manufacture
Combination product manufacturing applies to the entire combination product (e.g., drug
–device combination) in accordance with 21 CFR Part 4. 35 In Section 3.2.P.3 include
applicable device information pertaining to manufacturing or assembly of the finished
combination product as a whole. As applicable, this section may hyperlink to unique
device constituent manufacturing information in 3.2.R.
i.
Section 3.2.P.3.1 Manufacturer(s)
•
•
•
ii.
For each facility identify the type of manufacturing and testing activities that
occur
For each facility that is subject to 21 CFR part 4, identity whether it follows the
combination product streamlined manufacturing approach and identify the base
set of regulations (i.e., 21 CFR 211 or 820).
Provide a detailed list of all manufacturing facilities; what activities occur at the
site (e.g., assembly, filling, sterilization, testing, other); what constituents are at
the site (e.g., drug only, device only, both drug and device). For the facilities
that have both the drug and device, identify which combination product
operating system is used at the site.
Section 3.2.P.3.2 Batch Formula (nm, df)
Use this section to describe only the drug components and composition.
iii.
Section 3.2.P.3.3 Description of Manufacturing Process and Process Controls
(nm, df)
This section would contain any submitted general descriptions/summaries. It
may cross-reference to Section 3.2.R to support the manufacturing process.
•
•
•
•
b.
Management Controls
Design Control, General
Purchasing Controls
Corrective Action
Section 3.2.P.5 Drug Product
Section 3.2.P.5, should usually be an element of a repeated section, as appropriate. The
first 3.2.P Drug Product section would be for the drug product (e.g., “midazolam
injection”). The second 3.2.P Drug Product section might be for the final combination
product lot release specifications that include the specification requirements for the device
constituent (e.g. “midazolam pre-filled syringe”). These specifications should rely on the
21 CFR Part 4 “Current Good Manufacturing Practice Requirements for Combination Products” is accessible at
https://www.federalregister.gov/documents/2013/01/22/2013-01068/current-good-manufacturing-practicerequirements-for-combination-products
35
30
device design transfer data (see design control information) and should link to the
supporting eCTD data section, e.g., in Section 3.2.R.
c.
Section 3.2.P.7 Container Closure System
Continue to use this section for devices that serve as primary or secondary container
closure. Please refer to FDA guidance on Container Closure for additional information. 36
This section may link to Section 3.2.R as appropriate for device constituent testing.
d.
Section 3.2.R Regional Information
This section may be used for device engineering design documentation and narrative
explanations that are not otherwise provided in Section 3.2.P.7. Examples of the
information include the following:
A. Design Input Requirements
B. Design Output Specifications (e.g., device description, drawings, specifications, bill
of materials, etc.)
C. Design Verification Plan/Summary Report and supporting data (e.g., software,
electromechanical conformance, bench testing, biocompatibility)
D. Design Validation Plan/Summary Report and supporting data (e.g., performance
testing, narrative discussion of the applicability of data provided in Module 5).
E. Risk Management File
F. Traceability Matrix
Note: Section 3.2 R does not provide for subordinate sections. Every file is listed under a
common heading. Document titles should be clear, concise and indicative of the
document's content. See Section 2.3.4 of this guide for additional information on
document titles. In this section, for device related files, each document title should be
prefixed with “DEVICE:”
5. Module 5
Human Factors Validation Study results for the combination product should be placed in
eCTD Section 5.3.5.4 Other Study Reports with links from appropriate Module 3 files,
and include the code for the appropriate human factors document type keywords (e.g.,
hf validation protocol, hf validation report, hf validation other). The code values for
these document type keywords should be provided when the relevant content is
submitted.
Additionally, a cross-reference (e.g., hyperlink) of the submission contents from Module
5 to Module 3 may be made, as applicable.
Guidance to Industry: Container Closure Systems for Packaging Human Drugs and Biologics;
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/container-closure-systems-packaginghuman-drugs-and-biologics
36
31
5.
APPENDIX A: RULES FOR SUBMISSION TRACKING
INFORMATION
The following tables outline the allowable submission tracking information for the submission
unit, submission, and application.
Table 2: Submission Type and Descriptions of Use
Submission Type
Submission
Valid For
Unit Types
Application Types
Original Application
Presubmission
IND, NDA, ANDA,
Application
BLA, MF, EUA
Amendment
Resubmission
Efficacy Supplement
Presubmission
NDA, BLA
Application
Amendment
Resubmission
Chemistry
Presubmission
NDA, ANDA, BLA
Manufacturing
Application
Controls Supplement
Amendment
Resubmission
Labeling Supplement
Presubmission
NDA, ANDA, BLA
Application
Amendment
Resubmission
Annual Report
Report
IND, NDA, ANDA,
Amendment
BLA, MF
Product
Correspondence
IND, NDA, ANDA,
Correspondence
Amendment
BLA, MF
Postmarketing
Original
NDA, BLA
Requirements or
Amendment
Postmarketing
Commitments
Promotional Labeling Original
NDA, ANDA, BLA
Advertising
Resubmission
Amendment
IND Safety Reports
Report
IND
Amendment
32
Submission Type
Periodic Safety
Reports (Periodic
Adverse Drug
Experience Report
(PADER) or
Periodic Safety
Update Report
(PSUR))
REMS Supplement
Submission
Unit Types
Report
Amendment
Valid For
Application Types
NDA, ANDA, BLA
Application
Amendment
Resubmission
NDA, ANDA, BLA
Table 3: Submission Unit Type and Descriptions of Use
Submission Unit Description
Valid For the Listed
Type
Submission Types
Presubmission
A submission to the Agency that
Original Application,
occurs prior to the actual submission Efficacy Supplement,
of a full application (e.g., rolling
Chemistry Manufacturing
review, reviewable unit, clinical
Controls Supplement,
information that the applicant
Labeling Supplement
requests comment on prior to
submitting their application). Not all
applications will have
presubmissions.
Application
The submission that represents the
Original Application,
application’s primary supportive
Efficacy Supplement,
material. There should only be one
Chemistry Manufacturing
submission with a sub-type of
Controls Supplement,
application within a given
Labeling Supplement,
submission group.
REMS Supplement
Amendment
A submission that contains additional
supportive material to augment
information previously submitted.
Examples include responses to
information requests, additional draft
labeling during negotiations, etc.
33
Original Application,
Efficacy Supplement,
Chemistry Manufacturing
Controls Supplement,
REMS Supplement,
Annual Report,
Product Correspondence,
Postmarketing
Requirements or
Postmarketing
Commitments,
Promotional Labeling
Submission Unit
Type
Resubmission
Description
Valid For the Listed
Submission Types
Advertising,
IND Safety Reports,
Periodic Safety Reports
(Periodic Adverse Drug
Experience Report
(PADER) or
Periodic Safety Update
Report (PSUR)
A submission that contains additional Original Application,
information for the Agency to
Efficacy Supplement,
consider following the issuance of an Chemistry Manufacturing
action communication to the
Controls Supplement,
applicant (e.g., complete response or Labeling Supplement,
inactivation).
REMS Supplement,
Promotional Labeling
For promotional labeling and
Advertising
advertising, the submission of
revised promotional materials that
were previously submitted as an
original submission sub-type.
Includes requests for advisory on
launch materials, requests for
advisory on nonlaunch materials,
pre-submission of promotional
materials for accelerated approval
products, and materials submitted
under the Pre-Dissemination Review
of Television Ads Program.
Report
A submission that contains a new
annual report, IND Safety Report, or
Periodic Safety Report (Periodic
Adverse Drug Experience Report
(PADER) or Periodic Safety Update
Report (PSUR)).
Annual Report,
IND Safety Reports,
Periodic Safety Reports
(Periodic Adverse Drug
Experience Report
(PADER) or
Periodic Safety Update
Report (PSUR))
Original
Submission of original promotional
materials including all promotional
labeling and advertising submissions,
or Postmarketing Requirements or
Postmarketing Commitments
Promotional Labeling
Advertising,
Postmarketing
Requirements or
Postmarketing
Commitments
34
Submission Unit
Type
Correspondence
Description
Routine: administrative changes,
e.g., change of address, authorized
official, or meeting requests.
Donor re-entry request: An
applicant’s request to re-enter a
deferred donor when regulations
and/or guidance do not provide a
qualification method or process for
their specific situation. (21 CFR
610.41(b))
License re-issuance: request from
applicant to change legal name.
Lot distribution report:
Postmarketing report required by 21
CFR 600.81 to be submitted every
six (6) months upon
approval/licensing of vaccine or
biologic product.
Final labeling
35
Valid For the Listed
Submission Types
Product Correspondence
6.
REFERENCES
The following are technical specifications documents incorporated by reference into the guidance
for industry Providing Regulatory Submissions in Electronic Format — Certain Human
Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications.
These documents are located on the FDA eCTD Web page at: https://www.fda.gov/ectd.
1. ICH eCTD v4.0 Implementation Package (also accessible at https://www.ich.org/page/ichelectronic-common-technical-document-ectd-v40)
2. FDA technical specification, FDA eCTD v4.0 Module 1 Implementation Package
3. FDA guidance for industry, M4 Organization of the Common Technical Document for the
Registration of Pharmaceuticals for Human Use
4. ICH M8 technical specification, eCTD v4.0 IWG Question and Answer and Specification
Change Request Document
5. FDA technical specification, FDA eCTD v4.0 Table of Contents Headings and Hierarchy
6. FDA technical specification, Specifications for File Format Types Using eCTD Specifications
7. FDA technical specification, FDA Portable Document Format (PDF) Specifications
8. FDA guidance for industry, Integrated Summaries of Effectiveness and Safety: Location
Within the Common Technical Document
9. FDA technical specification, Transmission Specifications, Specification for Transmitting
Electronic Submissions Using eCTD Specifications
10. FDA technical specification, eCTD Validation Specifications, Specifications for eCTD v4.0
Validation Criteria
36
7.
RELATED REFERENCES
The following references are relevant to the content in this document, but are not explicitly
referenced.
1. FDA guidance for industry, Providing Regulatory Submissions in Electronic Format Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic Act (accessible
at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
under Electronic Submissions)
2. FDA guidance for industry, Providing Regulatory Submissions in Electronic Format Standardized Study Data (accessible at https://www.fda.gov/drugs/guidance-complianceregulatory-information/guidances-drugs under Electronic Submissions)
3. FDA guidance for industry, Providing Regulatory Submissions in Electronic Format - Receipt
Dates (accessible at https://www.fda.gov/drugs/guidance-compliance-regulatoryinformation/guidances-drugs under Electronic Submissions)
4. FDA guidance for industry, M4: The CTD - Quality, Questions and Answers/Location Issues
(accessible at https://www.fda.gov/drugs/guidance-compliance-regulatoryinformation/guidances-drugs under ICH-Multidisciplinary)
5. FDA guidance for industry, Sponsor Responsibilities—Safety Reporting Requirements and
Safety Assessment for IND and Bioavailability/Bioequivalence Studies (accessible at
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
under Safety - Issues, Errors, and Problems)
37